Transcriptomic and epigenetic profiling of genome control in the germline stem cell cycle in mice [ChIP-seq II]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139677 | GEO | 2020/02/06
REPOSITORIES: GEO
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Project description:The faithful transmission of genome information is fundamental to the germline stem cell cycle. One exception to this is meiosis when active recombination takes place. This study aims to understand how dna damage responses and meiotic recombination mechanisms are properly coordinated with developmental programs of germ cells by comparing transcriptomic and epigenetic profiles of germline competent pluripotent stem cells, germline stem cells and somatic cells etc. in mice.
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Project description:The faithful transmission of genome information is fundamental to the germline stem cell cycle. One exception to this is meiosis when active recombination takes place. This study aims to understand how dna damage responses and meiotic recombination mechanisms are properly coordinated with developmental programs of germ cells by comparing transcriptomic and epigenetic profiles of germline competent pluripotent stem cells, germline stem cells and somatic cells etc. in mice.
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Project description:Nascent human primordial germ cell-like cells (PGCLCs) can be specified with BMP2 or BMP4 together with SCF and EGF from germline competent embryonic stem cells which are maintained in the presence of inhibitors for GSK3, MEK, p38 and JNK together with FGF2, TGFβ and LIF (4i ESC). Here we discovered that Activin A and retinoic acid treatment after PGC specification induced genes expressed in migrating and gonadal PGCs in vivo, including DMRT1 and CDH5. Ectopic expression of DMRT1 and SOX17 resulted in repression of pluripotent genes as well as induction of DAZL and a subset of mitotic arrest PGC genes. Our findings provide novel insights on the roles of DMRT1 for the transition from nascent PGCs towards germline determination and molecular mechanisms of early human germline development.
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Project description:Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1 deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.
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